Tag: research

I have spent a little time introducing and reviewing New Daily Persistent Headache (NDPH), and what a miserable headache it is. We know that traditional headache medications and treatments are not particularly useful in alleviating NDPH. But there are some new initiatives available, some research initiatives and novel approaches to NDPH treatment which may bring some positive answers. I happen to be involved in a research project funded by the Migraine Research Foundation and also in a novel treatment approach to treating NDPH at our tertiary pediatric headache clinic. So while it can be disheartening to care for kids with this diagnosis, it can also be hopeful, if you can identify something that might just help.

Because NDPH often appears after a viral illness, some researchers have posited that the headache is part of a post-inflammatory or autoimmune response. It is also a chronic pain entity, so treatments used for chronic pain might be useful (chronic regional pain syndrome (CRPS) or fibromyalgia). Treatment options now being considered are those that reduce inflammation in the body, such as low-dose naltrexone, anti-inflammatory diets, and short duration lidocaine infusion.

Here are some of the ideas that are being researched concerning NDPH:

Research initiative: Endogenous Modulation and Central Sensitization in New Daily Persistent Headache (NDPH) in Children, Boston Children’s Hospital, Pediatric Headache Program. This project has started and recruitment is ongoing. The aims of this research are:

Psychophysical Characterization of NDPH: To define differences in altered modulatory systems using offset analgesia in well characterized NDPH pediatric patients in the symptomatic and recovered state.

Treatment Effects in NDPH: To define the effects of low-dose naltrexone on offset analgesia.

The proposed work would be the first comprehensive, study of pediatric NDPH. If successful it will provide insights into altered modulatory systems in the disease and define for the first time potential insights into mechanisms underlying chronicity vs. response.

Research initiative: Analysis of Headache Chronification with Imaging, Deep Phenotyping, and Proteomics, Stanford University School of Medicine

The purpose of this study is to better understand disease processes and risk factors involved in onset of chronic daily headaches/Chronic Migraines. They hope to learn more about the basic pathophysiology and neuromodulation of NDPH to determine effective treatment strategies and prophylactic measures.

Participation in this research study includes online questionnaires, a blood sample, a lumbar puncture, and a magnetic resonance imaging (MRI) scan without contrast to measure brain activity. This study was started in 2014, will continue until 2020, for patients over the age of 18 years.

This research is studying whether CGRP or NGF levels are elevated in the plasma of New Daily Persistent Headache patients compared to those with chronic migraine and normal controls. This study is ongoing, for patients over age 18 years.

Treatment: Botox for NDPH: Recent reports from the Cleveland Clinic and Case Western Reserve describe patients with new daily persistent headaches (NDPH) who were treated with Botox injections (standard Botox for chronic migraine protocol). The improvement was modest (30%), with some reduction in headache pain, headache-free days not previously experienced, and positive effects lasting for 8 weeks. Available for patients over 18 years, and pending insurance approval (not FDA approved for this indication).

Treatment: Low dose naltrexone: Naltrexone is an anti-inflammatory agent, similar to the opioid antagonist naloxone, and an effective treatment for opioid addiction. It was recently discovered that when taken in low doses (1/10 of the typical dose), it may reduce the severity of chronic pain symptoms, by acting on the glial cells and other receptors in the nervous system. Because of its analgesic property, low-dose naltrexone may be an effective treatment for the management of several chronic pain conditions, including fibromyalgia and chronic headache. More research needs to be done to evaluate long-term effects of using low-dose naltrexone, and to assess the efficacy and safety of this medication in the treatment of patients with NDPH. If prescribed, this medication has to be prepared at a compounding pharmacy; retail pharmacies carry the standard 50mg tabs, and low-dose naltrexone is dosed at 4.5mg, which requires compounding, usually not covered by insurance.

Treatment: Short-duration lidocaine infusion: Lidocaine has been used as anesthesia and analgesia for more than 50 years, and is very effective at relieving nerve pain, chronic pain syndromes, and pain after surgery. Lidocaine is an amide local anesthetic agent, which blocks fast voltage-gated sodium channels in the cell membrane of postsynaptic neurons, preventing depolarization and inhibiting the generation and propagation of nerve impulses. Basically, lidocaine stops pain impulses from going to and from the brain, so pain is blocked.

In my pediatric headache program, we now offer short duration lidocaine infusions to our patients with New Daily Persistent Headache, the first program doing this with pediatric patients. It has been used in adult pain programs for chronic pain for many years. We hoped it would be effective for teens with NDPH, also a chronic pain condition, providing a decrease in pain level and/or reduction in the associated symptoms for these patients.

The protocol for short duration lidocaine infusion for patients over 50kg is 200mg of lidocaine IV over 2 hours , with appropriate monitoring for alterations in cardiac status and signs of lidocaine toxicity. For patients less than 50kg, 4mg/kg is given. At first, we did a bolus dose of 100mg over 30 minutes, followed by an infusion of the remaining 100mg over 1 hour. Unfortunately, in the 1st 3 months, almost all of the kids had side effects during the bolus. So we changed to a 2 hour infusion which has been much better tolerated, many fewer reactions.

So what are the results? Well at first we were disappointed because there was really minimal reduction in headache pain. Then, it became clear that the benefits were more significant in reducing the other symptoms. In particular, patients were achieving improvement in their persistent nausea, dizziness, difficulty with concentration, difficulty with physical activity, mental clouding, fatigue and overall functioning. And for the majority of patients who responded positively, they did not return all the way to baseline after several months, with sustained improvement. We have a number of patients who come in every 3 months and repeat the infusion because it has benefitted them so much. What the kids tell me is that they can actually tolerate the headache pain, when the other symptoms are reduced, but have a great deal of trouble functioning with both headache and the rest of their symptoms. I think the kids who have many associated symptoms seem to get the most benefit and improvement. I will put a copy of the poster abstract we did about this- preliminary results over the first year- in resources.

This is an initiative I am quite involved with, screening, monitoring during infusion and follow up with data collection. It is exciting to find something that is showing benefit to my kids with NDPH. Granted, we only have about 60% positive response rate, but for those 60%, it is wonderful.

We will be continuing this initiative and collecting data and at some point be putting together an academic paper to share. I am also hopeful that some of the research work will also yield positive results. At the very least a better understanding of the pathophysiology of NDPH would help guide future therapies.

I will discuss more about NDPH trajectory for resolution and other matters in the next post.

Let’s talk today about the story of NDPH, a primary headache not well understood or recognized, a zebra among headaches. The more we know about it, the more it is recognized. But that does not make it any easier to deal with as a provider or a patient.

The first documented description of NDPH was in 1986, by Dr. Walter Vanast, a neurologist in Canada. He described it as a benign syndrome that resolved regardless of treatment in 73-86% in 3-24 months. In a recent interview with Dr. Vanast in Headache journal, he describes his interest and search for the cause of this headache. He thought it was an auto‐immune disorder with a persistent viral trigger, such as EBV. And this description is still in use today, though in my opinion ‘benign’ is not the word I would use.

About half of patients with NDPH have had a febrile viral illness near the onset. Others develop it after a minor head injury, or pseudotumor or idiopathic intracranial hypertension (IIH). Others seem to have no known reason for this headache to develop. There continues to be very little known about the pathophysiology of NDPH. A recent paper stated that it might be related to persistent central nervous system inflammation or related to cervical hypermobility. We really don’t know.

The incidence in adult of chronic daily headache is 4%; the incidence of these adult patients having NDPH is between 1-10%, so not that many. But in children and teens, the incidence is much higher: 20-40% of pediatric chronic daily headache patients. Way more kids and teens than adults have NDPH. And it is probably underreported and under recognized.

There are several different patterns of headache associated with NDPH.

The first type is mild and self-limiting, resolving without therapy.

The second type is moderate, with a constant headache that waxes and wanes over time. Good days are more like tension-type headaches and bad days are more like migraine.

The third type is a continuous severe headache, with disabling high-level pain all day every day.

We don’t see many patients with the first type, with lower level headaches that just end up going away. Most commonly we see the second type, kids with constant all day every day headache, pain rated 5-6/10NRS on average with a range of 3-9/10NRS. On lower pain days, they might have mild nausea, mild dizziness, mild mental fogginess and light sensitivity along with headache. On higher pain days, all of their symptoms are severe and migrainous; pain is 8-9/10NRS, and they are non-functional. Their pain and symptoms are disabling; change in pain level is influenced by activity, weather patterns, stress and cognitive effort. Fortunately, while we do see the completely refractory third type, they are not as common– but so difficult.

So it is hard enough to have a constant headache, no headache-free time. But add to that is the realization that most common treatments and even the most aggressive treatments are ineffective against this headache. Current daily medications do not alleviate their pain and the patients just experience all the side effects.

Usually by the time the patient arrives at our specialty headache program, they have already tried at least 1 or more daily medications without success. The families might like to try more medication, so we would pick another of the common ones. The choice is often based on what other symptoms are most bothersome.

Unable to sleep? Choose amitriptyline or gabapentin.

Worried about weight gain? Choose topiramate.

Don’t want any mental clouding? Try propranolol.

Super dizzy? Try verapamil.

Persistent nausea? Add hydroxyzine at bedtime.

Very tight neck and upper back muscle? Choose tizanidine.

Don’t want medications? Try a supplement- magnesium or riboflavin.

All else fails? Try occipital nerve and trigger point injections.

You might find that something helps other symptoms, even when it does nothing to the headache. I have had great results with using hydroxyzine at bedtime for patients with persistent nausea. Having less nausea may make the difference between going to school or staying home…. again.

It is just a matter of time before the families (really the patients) decide that they do not want to try any further medication, at least daily medication. Most tell me that they feel better off the meds.

Things you might try for a migraineur in status migrainosis such as going to the ED or being admitted for DHE are not usually helpful. Often the patients end up more frustrated, faced with another ineffective intervention.

As far as rescue medications, again you try the basics- NSAIDS, antiemetics, caffeine. Most important is to stress that analgesia should only be used for severe headache and no more than 3 days/week to avoid overuse headache. As you can imagine, overuse is tempting, kids just want to feel better. But I stress that too much analgesia will just make them feel worse, and in the end, the medications will stop working. I encourage being strategic with analgesia. Save it for when you might really need it, such as before SAT exams or before a big sports game or concert. This is generally effective in preventing overuse.

What is really important is for the families and patients to know that you are all in this together. Accepting where they are and working with them. Offering hope but being realistic.

I will have more to say about some research initiatives and novel approaches to NDPH in the next post.

So we have talked about lifestyle habits to prevent migraines, all the things your patient can do to prevent migraines. But your patient is still having frequent migraines or the migraines are significantly impacting the patient’s functioning. When do you consider adding a daily medication to prevent migraines? The mark I use for deciding when a preventive medication is needed is one migraine/week. For me, that is when the conversation needs to start. Any less than that, the kids may be unnecessarily exposed to medication effects and side effects.

And not every kid/teen needs to take a daily preventive medication, even when they have 1 migraine per week. It really depends on how much impact that migraine is having. Are they missing school with every migraine? Does the migraine last for several days, leading to even more missed school? Are they missing out on desired activities, like sports, scouts, music or dance? Are they missing out on time with friends and family? Does the patient want to try a daily medication? Is the family in favor or opposed to it? It is a choice that is made after discussion with everyone involved.

However, when the patient is having more than 1 migraine per week, it is a good idea to consider a daily medication, as it is likely that migraine is taking a toll of the patient and family. What you choose depends on the age of the patient and what other issues they are challenged with. Do you start with a prescribed medication or supplements/vitamins?

Supplements: If you and/or the family are on the fence about starting a medication, a nice intervention to add is a supplement known to help headaches. We commonly will recommend magnesium, riboflavin or Coenzyme Q10. I always advocate for using a single product at a time, taking it for at least 3 months and evaluating effectiveness. Again, you need to keep the good data. There are many combination products on the market. I have seen one which contains 10 supplements in one tab! The problem with combination products is that you are unable to figure out what exactly is helping, therefore are ‘married’ to a particular supplement formulation. And you know that’s going to end up being expensive. A good quality supplement, which can be obtained at the local pharmacy, is totally adequate to try and there are often opportunities to save money on them. These supplements are well tolerated and can be effective. Here’s a link: Supplements That Help Headaches

One supplement to mention is butterbur, a shrub grown in Europe and Asia, and used as a migraine preventive and for allergies. The concerns with butterbur are that it can be toxic to the liver; the unprocessed butterbur contains chemicals called pyrrolizidine alkaloids (PAs), which can cause liver damage. The only butterbur product you should use is labeled ‘PA- free’, meaning the PA has been processed to remove it. It is unlikely that you would ever find butterbur not labeled this way. Petadolex is the most common butterbur on the market and is PA-free. There are side effects as well such as belching and GI issues, and allergy and asthma, and people allergic to ragweed, chrysanthemums, marigold and daisies should avoid it. Butterbur has fallen out of favor due to report of hepatic issues, though a recent paper has refuted that claim. I have a few patients on it, tolerate it well, and find it helpful, when prescribed medications have not been. I check their LFTs yearly just to be sure. I mention it here to further your knowledge, as Dr. Google will be sure to mention it, when your families are searching for migraine remedies.

Medications: The aim of daily preventive medication is to decrease the frequency, duration and severity of migraines. Other benefits can include improving responsiveness to the rescue medications and preventing migraines from becoming chronic (vs. episodic). Your choice of medication depends on the patient’s age, medical history/comorbidities, and particular circumstances. Generally all migraine medications for kids and teens are dosed low and titrated up in dose as needed and tolerated. Groups of medications commonly used for migraine prevention are antihistamines (cyproheptadine), tricyclic antidepressants (amitriptyline, nortriptyline), anticonvulsants (topiramate, zonisamide, gabapentin), beta blockers (propranolol) or calcium channel blockers (verapamil).

Before we talk about the pros and cons of each group of medications, I would like to bring up an interesting research study you may or may not be aware of. A few years ago, the headache program at Cincinnati Children’s Hospital undertook a multi-site double blind medication trial, comparing amitriptyline, topiramate and placebo, for the prevention of migraine in children ages 8-17 years, the CHAMPS study. The headache program I work in participated in this research project. The study was unusual because it was double blind (no one knew which medication each subject was taking), and it included placebo as one of the treatment arms. The research study was terminated early because the findings showed no difference between the 3 treatments arms. The 2 medications both had more side effects than placebo, and there were also serious adverse events in each group. They conclude that “the risk to benefit profile of the two most commonly used preventive medications does not suggest their use as first-line intervention for pediatric migraine.” Basically, they found that placebo was as good as or better than medications and had fewer side effects. Here’s link to their results: CHAMPS clinical trial publication

This of course presents a dilemma to pediatric providers caring for kids with headaches. You can’t exactly prescribe a placebo and with the family knowing you are doing that, it negates the placebo effect. It is certainly another reason to continue doing research into pediatric headache, and to encourage our families to participate. We are doing a lot of research at our center, brain imaging, studies looking at the psychological factors impacting episodic and chronic pain, and clinical protocols. Our families are very interested in participating with research, as they see the value for themselves and for others.

When thinking about daily medications, we all need to be aware that studies are often not done on the pediatric population, just extrapolated from adult data. This is all the more reason to be cautious in prescribing, and encourage appropriate lifestyle measures to decrease the likelihood of migraine.

In my next post, I will review commonly used migraine preventive medications. Some pediatric providers may not feel comfortable starting a daily migraine preventive. But the judicious use of a low dose of medication may really help your patients with their migraines. It may prevent episodic migraine from becoming chronic, and prevent a functioning patient from becoming disabled. These are all worthy efforts.